Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial

Abstract

SummaryBackgroundPrimaquine and methylene blue are gametocytocidal compounds that could prevent Plasmodium falciparum transmission to mosquitoes. We aimed to assess the efficacy and safety of primaquine and methylene blue in preventing human to mosquito transmission of P falciparum among glucose-6-phosphate dehydrogenase (G6PD)-normal, gametocytaemic male participants.MethodsThis was a phase 2, single-blind, randomised controlled trial done at the Clinical Research Centre of the Malaria Research and Training Centre (MRTC) of the University of Bamako (Bamako, Mali). We enrolled male participants aged 5–50 years with asymptomatic P falciparum malaria. G6PD-normal participants with gametocytes detected by blood smear were randomised 1:1:1:1 in block sizes of eight, using a sealed-envelope design, to receive either sulfadoxine-pyrimethamine and amodiaquine, sulfadoxine-pyrimethamine and amodiaquine plus a single dose of 0·25 mg/kg primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus 15 mg/kg per day methylene blue for 3 days. Laboratory staff, investigators, and insectary technicians were masked to the treatment group and gametocyte density of study participants. The study pharmacist and treating physician were not masked. Participants could request unmasking. The primary efficacy endpoint, analysed in all infected patients with at least one infectivity measure before and after treatment, was median within-person percentage change in mosquito infectivity 2 and 7 days after treatment, assessed by membrane feeding. This study is registered with ClinicalTrials.gov, number NCT02831023.FindingsBetween June 27, 2016, and Nov 1, 2016, 80 participants were enrolled and assigned to the sulfadoxine-pyrimethamine and amodiaquine (n=20), sulfadoxine-pyrimethamine and amodiaquine plus primaquine (n=20), dihydroartemisinin-piperaquine (n=20), or dihydroartemisinin-piperaquine plus methylene blue (n=20) groups. Among participants infectious at baseline (54 [68%] of 80), those in the sulfadoxine-pyrimethamine and amodiaquine plus primaquine group (n=19) had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with sulfadoxine-pyrimethamine and amodiaquine alone (n=12; −10·2%, IQR −143·9 to 56·6; p<0·0001). The dihydroartemisinin-piperaquine plus methylene blue (n=11) group had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with dihydroartemisinin-piperaquine alone (n=12; −6·0%, IQR −126·1 to 86·9; p<0·0001). Haemoglobin changes were similar between gametocytocidal arms and their respective controls. After exclusion of blue urine, adverse events were similar across all groups (59 [74%] of 80 participants had 162 adverse events overall, 145 [90%] of which were mild).InterpretationAdding a single dose of 0·25 mg/kg primaquine to sulfadoxine-pyrimethamine and amodiaquine or 3 days of 15 mg/kg per day methylene blue to dihydroartemisinin-piperaquine was highly effi...

Persistence of P. Falciparum Ring-Stage Parasites 42 Days After Artemisinin and Non-Artemisinin Combination Therapy in Naturally Infected Malians

“…From a public health perspective, it is important to examine whether persisting ring-stage parasites are predictors of recrudescent infections or the source of gametocyte production. Our study population was small and as the original study objective was to assess gametocyte clearance and infectivity (14), not all individuals harbored asexual parasites at the start of treatment. Only 10 episodes of recurrent parasitemia were observed and only four of these represented recrudescent infections by conventional parasite genotyping.…”

“…This study used samples obtained from participants of a trial in Ouélessébougou, Mali who were randomized 1:1:1:1 to receive either sulfadoxine-pyrimethamine (SP-AQ), SP-AQ with single low-dose primaquine (SP-AQ + PQ), dihydroartemisinin-piperaquine (DP), or dihydroartemisinin-piperaquine with methylene blue (DP + MB) (14). Eligible participants were males with asymptomatic Plasmodium falciparum mono-infection, between 5 and 50 years of age, who were glucose-6-phosphate dehydrogenase (G6PD)-normal by CareStart G6PD rapid diagnostic test (Access Bio, Somerset, NJ, USA), had a hemoglobin concentration of ≥ 10 g/dL, and had a P. falciparum gametocyte density of ≥ 2 gametocytes/500 white blood cells by thick lm microscopy.…”

“…Details on the study procedures are described in the original paper (14). In brief, participants were followed for 42 days and blood samples were obtained on days 0, 1, 2, 7, 14, 28 and 42 after initiation of treatment.…”

“…Ring-stage parasites were quanti ed by qRT-PCR targeting the sbp1 mRNA transcript using previously described methods (6). Male and female gametocyte densities were quanti ed by qRT-PCR, targeting male PfMGET and female Pfs25 mRNA transcripts as described elsewhere (14). For samples that were microscopy-positive for asexual P. falciparum parasites on days 7, 14, 28, and 42, PCR genotyping of glurp (glurp2), msp2 (Fc27), msp1 (K1, MAD20 and RO33) and lc1 alleles were performed on samples obtained at enrollment and day of post-treatment failure.…”

Health-related publications on people living in fragile states in the alert zone: a bibliometric analysis

“…The other discussed infections such as Ebola, Cholera, and Onchocerciasis. The top ten cited articles were published in high impact journals, particularly The Lancet[38][39][40][41][42][43][44][45][46][47].…”